Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment.

Biochemical Pharmacology“Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities.

Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques.

Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is higly conserved in GPCRs.

In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.”

https://www.ncbi.nlm.nih.gov/pubmed/32360362

https://www.sciencedirect.com/science/article/abs/pii/S000629522030232X?via%3Dihub

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Cannabidiol attenuates behavioral changes in a rodent model of schizophrenia through 5-HT1A, but not CB1 and CB2 receptors.

Pharmacological Research“Preclinical and clinical data indicate that cannabidiol (CBD), a non-psychotomimetic compound from the Cannabis sativa plant, can induce antipsychotic-like effects.

These data suggest that CBD induces antipsychotic-like effects by activating 5-HT1A receptors and indicate that this compound could be an interesting alternative for the treatment of negative and cognitive symptoms of schizophrenia.”

https://www.ncbi.nlm.nih.gov/pubmed/32151683

https://www.sciencedirect.com/science/article/abs/pii/S1043661819315439?via%3Dihub

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Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects.

“Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fat-containing meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits.

A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebo-controlled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses.

Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/32103958

https://www.dovepress.com/cannabinoids-in-the-treatment-of-epilepsy-current-status-and-future-pr-peer-reviewed-article-NDT

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Cannabis and the exocannabinoid and endocannabinoid systems. Their use and controversies.

“Cannabis (marijuana) is one of the most consumed psychoactive substances in the world. The term marijuana is of Mexican origin. The primary cannabinoids that have been studied to date include cannabidiol and delta-9-tetrahydrocannabinol, which is responsible for most cannabis physical and psychotropic effects. Recently, the endocannabinoid system was discovered, which is made up of receptors, ligands and enzymes that are widely expressed in the brain and its periphery, where they act to maintain balance in several homeostatic processes. Exogenous cannabinoids or naturally-occurring phytocannabinoids interact with the endocannabinoid system. Marijuana must be processed in a laboratory to extract tetrahydrocannabinol and leave cannabidiol, which is the product that can be marketed. Some studies suggest cannabidiol has great potential for therapeutic use as an agent with antiepileptic, analgesic, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective properties; however, the findings on cannabinoids efficacy and cannabis-based medications tolerability-safety for some conditions are inconsistent. More scientific evidence is required in order to generate recommendations on the use of medicinal cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/32091020

http://gacetamedicademexico.com/frame_eng.php?id=348

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Cannabidiol as a treatment option for schizophrenia: recent evidence and current studies.

Image result for current opinion in psychiatry “The most recent studies published or initiated in the last 18 months, investigating cannabidiol in the treatment of symptoms of schizophrenia and related conditions are summarized, including observed tolerability and reported side-effects.

RECENT FINDINGS:

Recent studies focused on patients with sub-acute psychotic syndromes of schizophrenia, clinical high-risk state for psychosis (CHR-P), or frequent cannabis users, as well as cognitive functioning in chronic schizophrenia. There is further, although not consistent evidence for cannabidiol-reducing positive symptoms, but not negative symptoms. Evidence for improvement of cognition was weaker, with one study reporting a worsening. Regarding side effects and tolerability, cannabidiol induced sedation in one study, with the other studies indicating good tolerability, even at high doses.

SUMMARY:

Recent clinical trials added further evidence for an antipsychotic potential of cannabidiol. In general, studies following trial designs as suggested by regulators in schizophrenia are needed in sufficient numbers to clarify the safety and efficacy of cannabidiol herein. In addition, such studies will further elucidate its ability to target specific aspects of the syndrome, such as negative or cognitive symptoms. Furthermore, aiming for an add-on treatment with cannabidiol will require further studies to identify potentially useful or even harmful combinations.”

https://www.ncbi.nlm.nih.gov/pubmed/32073423

https://journals.lww.com/co-psychiatry/Abstract/publishahead/Cannabidiol_as_a_treatment_option_for.99134.aspx

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Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis.

 Image result for cambridge university press“Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown.

METHODS:

Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest.

RESULTS:

Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients.

CONCLUSIONS:

This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31994476

https://www.cambridge.org/core/journals/psychological-medicine/article/normalization-of-mediotemporal-and-prefrontal-activity-and-mediotemporalstriatal-connectivity-may-underlie-antipsychotic-effects-of-cannabidiol-in-psychosis/6571F47CE15D05DC50782A7BB7C00A7F

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Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis.

 “Stress is a risk factor for psychosis and treatments which mitigate its harmful effects are needed.

Cannabidiol (CBD) has antipsychotic and anxiolytic effects.

OBJECTIVES:

We investigated whether CBD would normalise the neuroendocrine and anxiety responses to stress in clinical high risk for psychosis (CHR) patients.

RESULTS:

One-way analysis of variance (ANOVA) revealed a significant effect of group (HC, CHR-P, CHR-CBD (p = .005) on cortisol reactivity as well as a significant (p = .003) linear decrease. The change in cortisol associated with experimental stress exposure was greatest in HC controls and least in CHR-P patients, with CHR-CBD patients exhibiting an intermediate response. Planned contrasts revealed that the cortisol reactivity was significantly different in HC compared with CHR-P (p = .003), and in HC compared with CHR-CBD (p = .014), but was not different between CHR-P and CHR-CBD (p = .70). Across the participant groups (CHR-P, CHR-CBD and HC), changes in anxiety and experience of public speaking stress (all p’s < .02) were greatest in the CHR-P and least in the HC, with CHR-CBD participants demonstrating an intermediate level of change.

CONCLUSIONS:

Our findings show that it is worthwhile to design further well powered studies which investigate whether CBD may be used to affect cortisol response in clinical high risk for psychosis patients and any effect this may have on symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/31915861

“Antipsychotic effects of CBD have been linked to its effects on levels of the endogenous cannabinoid anandamide (AEA) potentially by inhibiting its catalytic enzyme fatty acid amide hydrolase (FAAH). Recent preclinical work has also suggested that CBD may block the anxiogenic effects of chronic stress that was associated with a concomitant decrease in the expression of FAAH following CBD treatment. To the best of our knowledge, this is the first study to have investigated the effects of short-term treatment with CBD on experimentally induced stress in the context of psychosis risk. Notwithstanding its limitations, the present study provides a strong rationale for future studies to investigate whether CBD may have potential to mitigate the harmful effects of stress in the course of daily life by attenuating the altered neuroendocrine and psychological responses to acute stress in CHR participants.”

https://link.springer.com/article/10.1007%2Fs00213-019-05442-6

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Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats.

 Image result for Mol Neurobiol.“Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia.

The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration. In parallel, we assessed transcriptional changes behind CBD activities in the prefrontal cortex (PFC), the main brain area linked to schizophrenia-like pathologies.

Male Sprague-Dawley rats were injected for 10 days with KET followed by 6 days of CBD. The cognitive performance was evaluated in the novel object recognition test followed by PFC dissections for next-generation sequencing (RNA-Seq) analysis and bioinformatics.

We observed that KET-induced learning deficits were rescued by CBD (7.5 mg/kg).

Similarly, CBD reversed transcriptional changes induced by KET. The majority of the genes affected by KET and KET-CBD were allocated to astroglial and microglial cells and associated with immune-like processes mediating synaptogenesis and neuronal plasticity. These genes include C1qc, C1qa, C1qb, C2, and C3 complement cascade elements, Irf8 factor and Gpr84, Gpr34, Cx3cr1, P2ry12, and P2ry6 receptors. The main pathway regulators predicted to be involved included TGFβ1 and IFNγ. In addition, CBD itself upregulated oxytocin mRNA in the PFC.

The present data suggest that KET induces cognitive deficits and transcriptional changes in the PFC and that both effects are sensitive to a reversal by CBD treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31823199

https://link.springer.com/article/10.1007%2Fs12035-019-01831-2

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Cannabidiol as a potential treatment for psychosis

Image result for therapeutic advances in psychopharmacology“Accumulating evidence implicates the endocannabinoid system in the pathophysiology of psychosis.

If the endocannabinoid system plays a role in psychosis pathophysiology, it raises the interesting possibility that pharmacological compounds that modulate this system may have therapeutic value.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa, has been heralded as one such potential treatment.

Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has emerged as a potential novel class of antipsychotic with a unique mechanism of action.

In this review, we set out the prospects of CBD as a potential novel treatment for psychotic disorders.

In sum, CBD currently represents a promising potential novel treatment for patients with psychosis.”

https://journals.sagepub.com/doi/10.1177/2045125319881916

https://www.ncbi.nlm.nih.gov/pubmed/31741731

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Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis.

Image result for translational psychiatry “Accumulating evidence points towards the antipsychotic potential of cannabidiol. However, the neurocognitive mechanisms underlying the antipsychotic effect of cannabidiol remain unclear.

We investigated this in a double-blind, placebo-controlled, parallel-arm study. We investigated 33 antipsychotic-naïve subjects at clinical high risk for psychosis (CHR) randomised to 600 mg oral cannabidiol or placebo and compared them with 19 healthy controls.

We used the monetary incentive delay task while participants underwent fMRI to study reward processing, known to be abnormal in psychosis. Reward and loss anticipation phases were combined to examine a motivational salience condition and compared with neutral condition.

We observed abnormal activation in the left insula/parietal operculum in CHR participants given placebo compared to healthy controls associated with premature action initiation. Insular activation correlated with both positive psychotic symptoms and salience perception, as indexed by difference in reaction time between salient and neutral stimuli conditions.

CBD attenuated the increased activation in the left insula/parietal operculum and was associated with overall slowing of reaction time, suggesting a possible mechanism for its putative antipsychotic effect by normalising motivational salience and moderating motor response.”

https://www.ncbi.nlm.nih.gov/pubmed/31439831

https://www.nature.com/articles/s41398-019-0534-2

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